A matrix metalloprotease (MMP) is an endopeptidase playing a physiologically important role in tissue reconstruction, and its protease activity is under strict control. However, such control is disturbed in pathological conditions to induce an excessive degradation of the extracellular matrix, thus being involved pathogenically in articular diseases such as osteoarthritis and rheumatoid arthritis, bone diseases such as osteoporosis, periodontosis, tumor infiltration or metastasis, corneal ulceration and the like.
At least 15 types of MMPs are now known, and are classified based on their primary structure and substrate specificity into 5 groups consisting of the collagenase group (MMP-1, 8, 13), the gelatinase group (MMP-2, 9), the stromelysin group (MMP-3, 10), the membrane-type MMP group (MT1, 2, 3, 4-MMP) and the miscellaneous group (MMP-7, 11, 12, 18). Among these groups, MMP-13 in the collagenase group is reported to be expressed exclusively in cartilage and bone tissues and produced at a higher level in articular diseases.
In addition, MMP-13 is assumed to be deeply involved in bone or articular diseases due to its higher collagen degrading activity when compared with other collagenases.
A large number of MMP inhibitors have been reported (Current Pharmaceutical Design, 2, 624-661 (1996), Expert Opinion on Therapeutic Patents, 6, 1305-1315 (1996), and a large number of thiol derivatives were also reported recently (WO97-3783, WO97-38007, WO97-48685, EP818443, WO98-3164, WO98-3166, WO98-6696, WO98-8814, WO98-12211, WO98-23588, Bioorganic & Medicinal Chemistry Letters, 8, 1157-1162 (1998), Bioorganic &Medicinal Chemistry Letters, 8, 1163-1168 (1998)).
Those also reported in a large number are the compounds exhibiting inhibitory effects on MMP-13, which are classified broadly into hydroxamic acid derivatives (British Journal of Pharmacology, 121, 540-546 (1997), WO97-31892, WO98-15525, WO98-16506, WO98-16520), carboxylic acid derivatives (Journal of Clinical Investigation, 99, 1534-1545 (1997)-, WO98-6711, WO98-9934, WO98-17643) and thiol derivatives (WO98-3164, WO98-3166).
A novel compound which is more satisfactory when compared with conventional MMP inhibitors in terms of efficacy, duration and safety is desired.